Interferon Resistance of Emerging SARS-CoV-2 Variants
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Abstract
The emergence of SARS-CoV-2 variants with enhanced transmissibility, pathogenesis and resistance to vaccines presents urgent challenges for curbing the COVID-19 pandemic. While Spike mutations that enhance virus infectivity or neutralizing antibody evasion may drive the emergence of these novel variants, studies documenting a critical role for interferon responses in the early control of SARS-CoV-2 infection, combined with the presence of viral genes that limit these responses, suggest that interferons may also influence SARS-CoV-2 evolution. Here, we compared the potency of 17 different human interferons against multiple viral lineages sampled during the course of the global outbreak, including ancestral and four major variants of concern. Our data reveal increased interferon resistance in emerging SARS-CoV-2 variants, suggesting that evasion of innate immunity may be a significant, ongoing driving force for SARS-CoV-2 evolution. These findings have implications for the increased lethality of emerging variants and highlight the interferon subtypes that may be most successful in the treatment of early infections.
Author Summary
In less than 2 years since its spillover into humans, SARS-CoV-2 has infected over 220 million people, causing over 4.5 million COVID-19 deaths. High infection rates provided substantial opportunities for the virus to evolve, as variants with enhanced transmissibility, pathogenesis, and resistance to vaccine-elicited neutralizing antibodies have emerged. While much focus has centered on the Spike protein which the virus uses to infect target cells, mutations were also found in other viral proteins that might inhibit innate immune responses. Specifically, viruses encounter a potent innate immune response mediated by the interferons, two of which, IFNα2 and IFNβ, are being repurposed for COVID-19 treatment. Here, we compared the potency of human interferons against ancestral and emerging variants of SARS-CoV-2. Our data revealed increased interferon resistance in emerging SARS-CoV-2 strains that included the alpha, beta, gamma and delta variants of concern, suggesting a significant, but underappreciated role for innate immunity in driving the next phase of the COVID-19 pandemic.
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SciScore for 10.1101/2021.03.20.436257: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Cell lines: A549 cells were obtained from the American Type Culture Collection (ATCC) and cultured in complete media containing F-12 Ham’s media (Corning), 10% fetal bovine serum (Atlanta Biologicals), 1% penicillin/streptomycin/glutamine (Corning) and maintained at 37°C 5% CO2. A549suggested: NoneTo generate the A549-ACE2 stable cell line, 107 HEK293T (ATCC) cells in T-175 flasks were transiently co-transfected with 60 μg mixture of … SciScore for 10.1101/2021.03.20.436257: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Cell lines: A549 cells were obtained from the American Type Culture Collection (ATCC) and cultured in complete media containing F-12 Ham’s media (Corning), 10% fetal bovine serum (Atlanta Biologicals), 1% penicillin/streptomycin/glutamine (Corning) and maintained at 37°C 5% CO2. A549suggested: NoneTo generate the A549-ACE2 stable cell line, 107 HEK293T (ATCC) cells in T-175 flasks were transiently co-transfected with 60 μg mixture of pBABE-puro-ACE2, pUMVC, and pCMV-VSV-G at a 10:9:1 ratio using a calcium phosphate method42. HEK293Tsuggested: NoneThe contents of the entire vial (~0.5 ml) were inoculated into 3 T-75 flasks containing 3×106 A549-ACE2 cells, except for B.1.1.7 which was inoculated into 1 T-75 flask. A549-ACE2suggested: NoneSoftware and Algorithms Sentences Resources Statistical analyses: Data were analyzed using GraphPad Prism 8. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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